Defining nanoscopic structure-function relationship of α-Synuclein aggregates in neurodegenerative disorders

This study hypothesises that the clinical and pathologic features of each synucleinopathy disorder is encoded by a distinct conformation of the aggregated α-synuclein (αSyn).

Synucleinopathies, a subgroup of neurodegenerative diseases, are characterised by the deposition of αSyn aggregates in the central nervous system (CNS).

Most prevalent synucleinopathies are Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), Multiple System Atrophy (MSA).

Although αSyn deposition is observed in all of the synucleinopathies, it is not known why the same protein αSyn spread with distinct spatiotemporal patterns in the CNS for different synucleinopathies, targets different types of cell populations and ultimately leads to a spectrum of diseases with distinct clinical symptoms and variable rates of disease progression.

To explain this apparent paradox, I hypothesise that the molecular mechanism of αSyn aggregation is distinct for different synucleinopathies, and the structural and functional properties of aggregates generated in this aggregation are different.

To test this hypothesis, I will isolate αSyn aggregates from the postmortem of each synucleinopathy patients and recapitulate cell-type-specific seed-induced aggregation and spread in patient-derived cellular models.

Skin fibroblasts of synucleinopathy patients will be used to derive Neural Progenitor Cells, and these progenitor cells subsequently will be differentiated into distinct neurons and glial cells to mimic the CNS environment of each disease.

Using super-resolution based imaging, I will determine the structural and compositional features of individual αSyn species which form along the aggregation pathway and elucidate how these molecular structural and compositional features underpin the unique pathological abnormalities in PD, DLB and MSA.